Turnover of Murine Cytomegalovirus-Expanded CD8+ T Cells Is Similar to That of Memory Phenotype T Cells and Independent of the Magnitude of the Response.

The potential of memory T cells to provide protection against reinfection is beyond question. Yet, it remains debated whether long-term T cell memory is due to long-lived memory cells. There is ample evidence that blood-derived memory phenotype CD8+ T cells maintain themselves through cell division, rather than through longevity of individual cells. It has recently been proposed, however, that there may be heterogeneity in the lifespans of memory T cells, depending on factors such as exposure to cognate Ag. CMV infection induces not only conventional, contracting T cell responses, but also inflationary CD8+ T cell responses, which are maintained at unusually high numbers, and are even thought to continue to expand over time. It has been proposed that such inflating T cell responses result from the accumulation of relatively long-lived CMV-specific memory CD8+ T cells. Using in vivo deuterium labeling and mathematical modeling, we found that the average production rates and expected lifespans of mouse CMV-specific CD8+ T cells are very similar to those of bulk memory-phenotype CD8+ T cells. Even CMV-specific inflationary CD8+ T cell responses that differ 3-fold in size were found to turn over at similar rates.

Quantification of T-cell dynamics during latent cytomegalovirus infection in humans.

Cytomegalovirus (CMV) infection has a major impact on the T-cell pool, which is thought to be associated with ageing of the immune system. The effect on the T-cell pool has been interpreted as an effect of CMV on non-CMV specific T-cells. However, it remains unclear whether the effect of CMV could simply be explained by the presence of large, immunodominant, CMV-specific memory CD8+ T-cell populations. These have been suggested to establish through gradual accumulation of long-lived cells. However, little is known about their maintenance. We investigated the effect of CMV infection on T-cell dynamics in healthy older adults, and aimed to unravel the mechanisms of maintenance of large numbers of CMV-specific CD8+ T-cells. We studied the expression of senescence, proliferation, and apoptosis markers and quantified the in vivo dynamics of CMV-specific and other memory T-cell populations using in vivo deuterium labelling. Increased expression of late-stage differentiation markers by CD8+ T-cells of CMV+ versus CMV- individuals was not solely explained by the presence of large, immunodominant CMV-specific CD8+ T-cell populations. The lifespans of circulating CMV-specific CD8+ T-cells did not differ significantly from those of bulk memory CD8+ T-cells, and the lifespans of bulk memory CD8+ T-cells did not differ significantly between CMV- and CMV+ individuals. Memory CD4+ T-cells of CMV+ individuals showed increased expression of late-stage differentiation markers and decreased Ki-67 expression. Overall, the expression of senescence markers on T-cell populations correlated positively with their expected in vivo lifespan. Together, this work suggests that i) large, immunodominant CMV-specific CD8+ T-cell populations do not explain the phenotypical differences between CMV+ and CMV- individuals, ii) CMV infection hardly affects the dynamics of the T-cell pool, and iii) large numbers of CMV-specific CD8+ T-cells are not due to longer lifespans of these cells.

Maintenance of peripheral naive T cells is sustained by thymus output in mice but not humans.

Parallels between T cell kinetics in mice and men have fueled the idea that a young mouse is a good model system for a young human, and an old mouse, for an elderly human. By combining in vivo kinetic labeling using deuterated water, thymectomy experiments, analysis of T cell receptor excision circles and CD31 expression, and mathematical modeling, we have quantified the contribution of thymus output and peripheral naive T cell division to the maintenance of T cells in mice and men. Aging affected naive T cell maintenance fundamentally differently in mice and men. Whereas the naive T cell pool in mice was almost exclusively sustained by thymus output throughout their lifetime, the maintenance of the adult human naive T cell pool occurred almost exclusively through peripheral T cell division. These findings put constraints on the extrapolation of insights into T cell dynamics from mouse to man and vice versa.

Long-term restoration of the human T-cell compartment after thymectomy during infancy: a role for thymic regeneration?

Thymectomy during early childhood is generally thought to have serious consequences for the establishment of the T-cell compartment. In the present study, we investigated the composition of the T-cell pool in the first 3 decades after thymectomy during infancy due to cardiac surgery. In the first 5 years after thymectomy, naive and total CD4(+) and CD8(+) T-cell numbers in the blood and T-cell receptor excision circle (TREC) levels in CD4(+) T cells were significantly lower than in healthy age-matched controls. In the first years after thymectomy, plasma IL-7 levels were significantly elevated and peripheral T-cell proliferation levels were increased by ∼ 2-fold. From 5 years after thymectomy onward, naive CD4(+) and CD8(+) T-cell counts and TRECs were within the normal range. Because TREC levels are expected to decline continuously in the absence of thymic output, we investigated whether normalization of the naive T-cell pool could be due to regeneration of thymic tissue. In the majority of individuals who had been thymectomized during infancy, thymic tissue could indeed be identified on magnetic resonance imaging scans. Whereas thymectomy has severe effects on the establishment of the naive T-cell compartment during early childhood, our data suggest that functional regrowth of thymic tissue can limit its effects in subsequent years.

Decreased thymic output accounts for decreased naive T cell numbers in children with Down syndrome.

Children with Down syndrome (DS) have low numbers of naive T cells and abnormal thymus development and function. Because next to thymic production, peripheral proliferation greatly contributes to naive T cell generation in healthy children, we examined the cause of reduced naive T cell numbers in children with DS. Compared with aged matched controls, the total number of signal joint TCR excision circles (sjTREC) per ml blood was reduced in DS. Reduced frequencies and absolute numbers of protein tyrosine kinase 7-positive recent thymic emigrants, but similar levels of naive T cell apoptosis and Ag-driven activation in DS, suggested that reduced thymic output and not increased peripheral loss of naive T cells caused the reduced sjTREC numbers. We found no support for defective peripheral generation of naive T cells in DS. In DS the naive T cells responded to IL-7 and, based on Ki-67 expression, had similar proliferation rates as in healthy controls. sjTREC content per naive CD8(+) T cells was not increased, but even decreased, pointing to increased survival or peripheral generation of naive T cells in DS. In conclusion, we show in this study that reduced thymic output, but not reduced peripheral generation nor increased loss of naive T cells, results in the low naive T cell numbers found in DS.

Immune reconstitution in children following chemotherapy for haematological malignancies: a long-term follow-up.

Modern intensive chemotherapy for childhood haematological malignancies has led to high cure rates, but has detrimental effects on the immune system. There is little knowledge concerning long-term recovery of the adaptive immune system. Here we studied the long-term reconstitution of the adaptive immune system in 31 children treated for haematological malignancies between July 2000 and October 2006. We performed detailed phenotypical and functional analyses of the various B and T cell subpopulations until 5 years after chemotherapy. We show that recovery of newly-developed transitional B cells and naive B and T cells occurred rapidly, within months, whereas recovery of the different memory B and T cell subpopulations was slower and incomplete, even after 5 years post-chemotherapy. The speed of B and T cell recovery was age-independent, despite a significant contribution of the thymus to T cell recovery. Plasmablast B cell levels remained above normal and immunoglobulin levels normalised within 1 week. Functional T cell responses were normal, even within the first year post-chemotherapy. This study shows that after intensive chemotherapy for haematological malignancies in children, numbers of several memory B and T cell subpopulations were decreased on the long term, while functional T cell responses were not compromised.

Cell-density independent increased lymphocyte production and loss rates post-autologous HSCT.

Lymphocyte numbers need to be quite tightly regulated. It is generally assumed that lymphocyte production and lifespan increase homeostatically when lymphocyte numbers are low and, vice versa, return to normal once cell numbers have normalized. This widely accepted concept is largely based on experiments in mice, but is hardly investigated in vivo in humans. Here we quantified lymphocyte production and loss rates in vivo in patients 0.5-1 year after their autologous hematopoietic stem cell transplantation (autoHSCT). We indeed found that the production rates of most T- and B-cell subsets in autoHSCT-patients were two to eight times higher than in healthy controls, but went hand in hand with a threefold to ninefold increase in cell loss rates. Both rates also did not normalize when cell numbers did. This shows that increased lymphocyte production and loss rates occur even long after autoHSCT and can persist in the face of apparently normal cell numbers.

Restoration of the CD4 T cell compartment after long-term highly active antiretroviral therapy without phenotypical signs of accelerated immunological aging.

It remains uncertain whether full T cell reconstitution can be established in HIV-infected children and adults with long-term sustained virological control by highly active antiretroviral therapy (HAART). In this study, we comprehensively analyzed various phenotypical markers of CD4 T cell recovery. In addition to measuring T cell activation and proliferation markers, CD4 T cell generation and aging of the CD4 T cell compartment were assessed by measuring TCR excision circles and the fraction of CD31-expressing naive CD4 T cells. In all children and in adults with relatively high CD4 T cell counts at start of therapy (>200 cells/microl), total CD4 T cell numbers normalized within 1 year of therapy. After long-term HAART (4.4-9.6 years), naive CD4 T cell counts had normalized in both groups. Although in adults with low baseline CD4 T cell counts (<200 cells/microl) total CD4 T cell numbers normalized eventually after at least 7 years of HAART, naive CD4 T cell counts had still not recovered. TCR excision circle data showed that thymic T cell production contributed to naive T cell recovery at all ages. The fraction of CD31-expressing naive CD4 T cells was found to be normal, suggesting that the CD4 T cell repertoire was diverse after long-term HAART. Hence, under sustained viral suppression during long-term HAART, the T cell compartment has the potential to fully recover by generating new naive T cells both in children and in adults with high baseline CD4 T cells counts. Irrespective of baseline CD4 T cell counts, reconstitution occurred without a significant effect on T cell aging as reflected by markers for replicative history.

In vivo deuterium labelling in mice supports a dynamic model for memory T-cell maintenance in the bone marrow.

The maintenance and dynamics of memory T-cells in the bone marrow are a matter of ongoing debate. It has been suggested that memory T-cells in the bone marrow are maintained as long-lived, quiescent cells. We have recently shown that memory T-cells isolated from goat bone marrow undergo self-renewal and recirculate via the blood and lymph. Using the well-established memory T-cell markers CD44 and CD62L we here show very similar results in mice. This provides further support for the concept that memory T-cells are continuously self-renewing and recirculating between blood, bone marrow, spleen and lymph nodes.

The effect of switching protease inhibitors to raltegravir on endothelial function, in HIV-infected patients.

Objective Lipid management is one of the cornerstones of cardiovascular risk reduction. Treatment of HIV infection with protease inhibitors (PIs) may cause dyslipidaemia, whilst the integrase inhibitor raltegravir (RAL) has a relatively favorable effect on plasma lipids. We examined the effect of switching from PIs to RAL on endothelial function, and its effect on immunological and inflammatory parameters. Methods We performed a 16-week open-label prospective crossover study: 8 weeks intervention (switch PIs to RAL) and 8 weeks control (unchanged cART regimen). Flow-mediated dilatation (FMD), inflammatory plasma, and cellular markers of immune activation were measured at weeks 0, 8, and 16. Results Study participants (n = 22) with a median age of 50 years (IQR 42-60) and known HIV infection of 6.5 years (IQR 5.0-17.3) were on stable cART with undetectable HIV viral loads. After 8 weeks of RAL therapy, a reduction in FMD of -0.81% was seen, compared to +0.54% control (pairwise, p = 0.051), while fasting total cholesterol (-17% versus +10%; p < 0.001), LDL cholesterol (-21% versus -3%; p = 0.026), and triglycerides (-41% versus +18%; p = 0.001) significantly decreased during RAL therapy compared to the control. Furthermore, a relation between the change in percentage of B-1 cells and the change in FMD was found (ß 0.40, 95%CI 0.16; 0.64, p = 0.005) during treatment with RAL. Finally, during RAL therapy, 27% of the patients experienced an increased ALT rise. Conclusions We present an overall negative study, where switching from PIs to RAL slightly reduced the endothelial function while decreasing plasma lipids, thus possibly decreasing the CVD risk in the long term. A transient elevation of ALT was seen upon switch to RAL.

Maraviroc Intensification Improves Endothelial Function in Abacavir-Treated Patients, an Open-Label Randomized Cross-Over Pilot Study.

BACKGROUND: The increased risk of abacavir in cardiovascular disease (CVD) in HIV-infected patients is still being debated. Maraviroc, a CCR5 blocker, has been shown to decrease immune activation and monocyte infiltration in atherosclerotic plaques in murine experiments. Therefore, we examined the effect of maraviroc intensification on flow-mediated dilatation (FMD) in abacavir-treated HIV-infected patients and its effect on immunological and inflammatory parameters. METHODS: A open-label prospective crossover study with a duration of 16 weeks: 8 weeks of intervention (maraviroc intensification) and 8 weeks of control (unchanged cART regimen). FMD, HIV-specific variables, expression of HIV co-receptors, markers of inflammation and coagulation and cellular markers of immune activation were measured at weeks 0, 8 and 16. The changes (Δ) in these variables were compared between intervention and control periods using non-parametric tests. To evaluate the relation with the change in FMD, linear regression modeling was used. RESULTS: Twenty-one male patients with suppressed plasma HIV-RNA, on cART, had a known HIV infection for 9.2 years (IQR 6.9-13.5) with abacavir use for 6.5 years (2.8-9.3). A significantly increased FMD of 0.73% (IQR -0.25 to 1.70) was seen after maraviroc intensification compared to a decrease of -0.42% (IQR -1.89 to 0.25; p = 0.049) in the control period. There was a negative relation between ΔFMD with ΔD-dimer (ß -22.70, 95% CI -39.27; -6.13, p = 0.011) and ΔCD95+ CD4+ T cells (ß -0.16, 95% CI -0.28; -0.04, p = 0.013), adjusted for age and duration of HIV. CONCLUSION: Maraviroc intensification modestly improves endothelial function in HIV-infected patients on an abacavir-containing regimen. TRIAL REGISTRATION: NCT01389063.

Reconciling Longitudinal Naive T-Cell and TREC Dynamics during HIV-1 Infection.

Naive T cells in untreated HIV-1 infected individuals have a reduced T-cell receptor excision circle (TREC) content. Previous mathematical models have suggested that this is due to increased naive T-cell division. It remains unclear, however, how reduced naive TREC contents can be reconciled with a gradual loss of naive T cells in HIV-1 infection. We performed longitudinal analyses in humans before and after HIV-1 seroconversion, and used a mathematical model to investigate which processes could explain the observed changes in naive T-cell numbers and TRECs during untreated HIV-1 disease progression. Both CD4+ and CD8+ naive T-cell TREC contents declined biphasically, with a rapid loss during the first year and a much slower loss during the chronic phase of infection. While naive CD8+ T-cell numbers hardly changed during follow-up, naive CD4+ T-cell counts continually declined. We show that a fine balance between increased T-cell division and loss in the peripheral naive T-cell pool can explain the observed short- and long-term changes in TRECs and naive T-cell numbers, especially if T-cell turnover during the acute phase is more increased than during the chronic phase of infection. Loss of thymic output, on the other hand, does not help to explain the biphasic loss of TRECs in HIV infection. The observed longitudinal changes in TRECs and naive T-cell numbers in HIV-infected individuals are most likely explained by a tight balance between increased T-cell division and death, suggesting that these changes are intrinsically linked in HIV infection.

Short communication: No detrimental immunological effects of mycophenolate mofetil and HAART in treatment-naive acute and chronic HIV-1-infected patients.

Mycophenolate mofetil has been proposed for HIV-1 therapy because of its guanine-depleting effect, which is expected to interfere with HIV-1 replication directly by hampering reverse transcription and indirectly via inhibition of CD4+ T cell proliferation. However, treatment with mycophenolate mofetil might also compromise lymphocyte reconstitution and HIV-specific immunity. Therefore we longitudinally studied the effects of mycophenolate mofetil in combination with HAART on T cell proliferation, lymphocyte reconstitution, and HIV-specific CD4+ and CD8+ T cell responses in six therapy-naive, acute or chronic HIV-1-infected patients, as compared to eight patients treated with HAART alone. T cell proliferation in whole blood cultures of patients treated with mycophenolate mofetil was inhibited. Strikingly, ex vivo Ki67 expression within T cells was not influenced by treatment with mycophenolate mofetil. In vitro studies showed that Ki67 expression occurs at an early step of the cell cycle and was not inhibited by guanine depletion. When treatment with mycophenolate mofetil was stopped a transient increase in apoptosis and Ki67-expressing T cells was detected. This observation together with near complete inhibition of T cell proliferation in whole blood cultures during treatment with mycophenolate mofetil indicated that T cell proliferation was inhibited in patients treated with mycophenolate mofetil. Still, there was no evidence for detrimental effects of treatment with mycophenolate mofetil in addition to HAART on CD4+ T cell reconstitution or HIV-specific immunity.

Quantification of naive and memory T-cell turnover during HIV-1 infection.

BACKGROUND: In HIV infection, the homeostasis of CD4 and CD8 T cells is dramatically disturbed, and several studies have pointed out that T-cell turnover rates are increased. To understand how the CD4 and CD8 T-cell pools are affected, it is important to have quantitative insights into the lifespans of the cells constituting the different T-lymphocyte populations. METHODS: We used long-term in-vivo H2O labeling and mathematical modeling to estimate the average lifespans of naive and memory CD4 and CD8 T cells in untreated (n = 4) and combination antiretroviral therapy-treated (n = 3) HIV-1-infected individuals. RESULTS: During untreated chronic HIV-1 infection, naive CD4 and CD8 T cells lived on average 618 and 271 days, whereas memory CD4 and CD8 T cells had average lifespans of 53 and 43 days, respectively. These lifespans were at least three-fold shorter than those in healthy controls (n = 5). In patients on effective combination antiretroviral therapy with total CD4 T-cell counts in the normal range, we found that naive CD4 and CD8 T-cell lifespans had not completely normalized and were still two-fold shortened. CONCLUSION: The average lifespan of both naive and memory CD4 and CD8 T cells decreased during untreated chronic HIV-1 infection. Although the turnover of the memory T-cell populations nearly normalized during effective treatment, the turnover of naive CD4 and CD8 T cells did not seem to normalize completely.

Maraviroc Intensification of cART in Patients with Suboptimal Immunological Recovery: A 48-Week, Placebo-Controlled Randomized Trial.

OBJECTIVE: The immunomodulatory effects of the CCR5-antagonist maraviroc might be beneficial in patients with a suboptimal immunological response, but results of different cART (combination antiretroviral therapy) intensification studies are conflicting. Therefore, we performed a 48-week placebo-controlled trial to determine the effect of maraviroc intensification on CD4+ T-cell counts and immune activation in these patients. DESIGN: Double-blind, placebo-controlled, randomized trial. METHODS: Major inclusion criteria were 1. CD4+ T-cell count <350 cells/µL while at least two years on cART or CD4+ T-cell count <200 cells/µL while at least one year on cART, and 2. viral suppression for at least the previous 6 months. HIV-infected patients were randomized to add maraviroc (41 patients) or placebo (44 patients) to their cART regimen for 48 weeks. Changes in CD4+ T-cell counts (primary endpoint) and other immunological parameters were modeled using linear mixed effects models. RESULTS: No significant differences for the modelled increase in CD4+ T-cell count (placebo 15.3 CD4+ T cells/µL (95% confidence interval (CI) [1.0, 29.5] versus maraviroc arm 22.9 CD4+ T cells/µL (95% CI [7.4, 38.5] p = 0.51) or alterations in the expression of markers for T-cell activation, proliferation and microbial translocation were found between the arms. However, maraviroc intensification did increase the percentage of CCR5 expressing CD4+ and CD8+ T-cells, and the plasma levels of the CCR5 ligand MIP-1ß. In contrast, the percentage of ex-vivo apoptotic CD8+ and CD4+ T-cells decreased in the maraviroc arm. CONCLUSIONS: Maraviroc intensification of cART did not increase CD4+ T-cell restoration or decrease immune activation as compared to placebo. However, ex-vivo T-cell apoptosis was decreased in the maraviroc arm. TRIAL REGISTRATION: ClinicalTrials.gov NCT00875368.

Discordant responses during antiretroviral therapy: role of immune activation and T cell redistribution rather than true CD4 T cell loss.

We studied T cell dynamics in four patients who initially responded well to highly active antiretroviral therapy (HAART) but subsequently experienced virological failure. Maintenance of peripheral blood CD4T cell counts was associated with low levels of immune activation. Low reactivity to rebounding virus may preserve normal T lymphocyte distribution over blood and tissues and be associated with stable peripheral blood T cell numbers in virological failures to HAART.

Pre-seroconversion immune status predicts the rate of CD4 T cell decline following HIV infection.

OBJECTIVE: To study whether immune status prior to HIV seroconversion predicts CD4 T cell decline during HIV infection. DESIGN: Prospective cohort study including 51 injecting drug users (IDU) who were HIV negative at study entry and seroconverted for HIV during follow-up. METHODS: Cryopreserved peripheral blood mononuclear cells obtained before HIV seroconversion were used to measure naive (CD45RO-CD27+), memory (CD45RO+CD27+), and total CD4 T cell numbers, the fraction of dividing Ki67+CD4+ T cells, and CD4 T cell receptor excision circles (TREC). The effect of pre-seroconversion immune status, as defined by these markers, on the rate of CD4 T cell decline during HIV infection was assessed using linear regression for repeated measurements. RESULTS: IDU with low pre-seroconversion CD4 T cell TREC contents lost CD4 T cells at a significantly faster rate during HIV infection than those with a high CD4 T cell TREC content. IDU with higher pre-seroconversion CD4 T cell numbers had a significantly steeper CD4 T cell decline in the first 3 months of HIV infection, but their CD4 T cell counts remained higher throughout HIV infection. Intermediate levels of pre-seroconversion dividing Ki67+CD4+ T cells were associated with a significantly steeper CD4 cell decline than high levels. IDU with the highest pre-seroconversion drug-injecting frequencies showed slower CD4 T cell decline than those who injected less. No correlation was present between pre-seroconversion immune markers and the pre-seroconversion duration or intensity of drug use. CONCLUSION: Among IDU, immune status prior to HIV infection as measured by TREC content affects the disease course after HIV seroconversion.

Depletion of naive CD4 T cells by CXCR4-using HIV-1 variants occurs mainly through increased T-cell death and activation.

OBJECTIVE: Using SCID-Hu mice models and in vitro culture systems, it has been shown that syncytium inducing/CXCR4 using (X4) HIV-1 variants affect thymic function through infection and killing of CXCR4 thymocytes. The effect of X4-emergence on naive, memory and effector T-cell subset kinetics in vivo is, however, not known. DESIGN: Prospective cohort study. METHODS: Analysis of changes in naive, memory and effector CD4 and CD8 T-cell numbers and cell division before and after the emergence of X4 variants. RESULTS: Significantly lower numbers of CD4 T cells in patients with X4 variants (n = 18) compared to patients with non-syncytium inducing/CCR5 using variants (n = 74) were due to increased loss of naive and CD27 memory CD4 T cells. In addition, emergence of X4 variants was associated with a small but significant decline in naive CD8 T-cell numbers and increased proportions of dividing CD4 and CD8 naive, memory and effector T cells. CONCLUSION: Loss of naive T cells may suggest thymic dysfunction, however, such an effect would explain only part of the accelerated naive CD4 T-cell decline because of the longevity of naive T cells. Our data suggest that the accelerated naive CD4 T-cell decline induced by X4 variants is caused mainly by increased death and recruitment to the memory compartment of these cells.

Persistent immune activation in HIV-1 infection is associated with progression to AIDS.

BACKGROUND: HIV-1 infection is characterized by chronic generalized CD8 and CD4 T cell hyperactivation, the biological effect of which is not understood. OBJECTIVE: To study the relation between chronic immune activation and CD4 T cell depletion in HIV-1 infection. DESIGN: Prospective cohort study among participants of the Amsterdam Cohort Studies on HIV-1 infection and AIDS who have a known seroconversion date (n = 102). METHODS: CD4 and CD8 T cell activation marker expression was analysed by FACScan before and after seroconversion (1 and 5 years after seroconversion); T cell proliferation and T cell numbers were also measured. Cox proportional hazard analyses were used to study the predictive value of these parameters for progression to AIDS. RESULTS: Preseroconversion low CD4 T cell numbers or elevated levels of CD4 T cell activation were associated with increased risk for development of AIDS after HIV-1 seroconversion. Progression to AIDS was associated with loss of both CD4 and CD8 naive T cells. The predictive value of CD8 T cell activation was confirmed and, in addition, in the course of infection low CD4 T cell counts and increasing proportions of dividing CD4 T cells, dividing CD8 T cells or elevated CD4 T cell activation marker expression became independent predictors of progression to AIDS. CONCLUSIONS: Increased T cell activation has predictive value for HIV-1 disease progression even before seroconversion. These data support the hypothesis that persistent hyperactivation of the immune system may lead to erosion of the naive T cell pool and CD4 T cell depletion.

Early viral load and CD4+ T cell count, but not percentage of CCR5+ or CXCR4+ CD4+ T cells, are associated with R5-to-X4 HIV type 1 virus evolution.

HIV-1 infection is established by CCR5-utilizing (R5) variants, and CXCR4-utilizing (X4) variants emerge in approximately 50% of infected patients. We studied the role of CCR5 and CXCR4 expression before and 1 and 5 years after seroconversion in HIV-1 disease in a prospective study of 102 seroconverters. High percentages of CCR5(+) cells among total cells (relative hazard [RH], 2.55; 95% confidence interval [95% CI], 0.99-6.52), but not among CD45RO(-)CD4(+) and CD45RO(+)CD4(+) cells preseroconversion and among total cells and CD45RO(-)CD4(+) cells (RH, 2.70; 95% CI, 1.06-6.92 and RH, 3.54; 95% CI, 1.27-9.90, respectively) 5 years after seroconversion were associated with more rapid progression to AIDS. One year after seroconversion, high percentages of CXCR4(+) cells among total and CD45RO(-)CD4(+) cells were associated with delayed development of X4 variants (RH, 0.49; 95% CI, 0.20-1.21 and RH, 0.41; 95% CI, 0.17-1.02, respectively), whereas no association was observed for the percentage of CCR5(+) cells. In a larger study population, high early serum viral RNA and low CD4(+) T cell numbers were associated with more rapid development of X4 variants. Our results exclude target cell availability as a driving force for R5-to-X4 virus phenotype evolution.